This invention relates generally to tablet coatings and to a method to prepare compositions useful to coat tablets. More particularly this invention relates to a tablet coated with gellan gum, use of gellan gum as a coating, a method to prepare a gellan gum composition useful to coat tablets, a gellan gum composition useful to coat tablet(s), and to a method for coating tablet(s) with gellan gum.
Tablets are typically used to deliver a pharmacologically effective amount of a therapeutic drug to humans and animals so as to provide medicinal benefit to the human or animal. Typically such therapeutically effective drugs include those drugs that possess and produce desirable drug effects after effective consumption by the human or animal.
In medicinal uses, one or more coatings is desired on a medicinal tablet in order to obtain one or more of gloss, better appearance, identification, mouthfeel, stability, color, swallowability, improved taste and the like.
Many medicinal tablet coatings today are low viscosity hydroxypropylmethylcellulose (HPMC). Usually a HPMC solution of about 10% weight with a viscosity below 1000 cps. (centipoise), with appropriate plasticizer, is applied by a spraying system or device to a tablet in a coating process.
Even with the foregoing and other tablet coating compositions, the industry continues to desire a product which provides enhanced tablet coating properties. The industry has recognized the need for an improved tablet coating which would provide increased gloss, better mouthfeel at coating quantities at lower levels than conventionally accepted methods, for example. The process of preparing such an improved tablet coating economically and efficiently continues to be of interest.
It is an objective of this invention to provide a tablet coating comprising gellan gum.
It is another objective of this invention to provide a tablet coated with gellan gum.
It is an additional objective of this invention to provide a process for preparing a gellan gum composition useful for coating tablets.
It is yet another objective of this invention to provide a process for preparing a coated tablet such as a coated placebo or a coated pharmaceutical tablet comprising an active drug.
It is yet still an additional objective of this invention to provide a tablet having one or more enhanced properties such as higher gloss, better mouthfeel, non-tackiness, being swallowable with little or no accompanying liquid, better taste and the like.
The above objectives and other objectives are met in this invention which is more particularly described hereinafter without limitation.
In one embodiment, this invention comprises a tablet coating comprising gellan gum. In another embodiment, this invention further comprises a placebo or an active drug or pharmaceutical wherein the placebo or drug is coated with gellan gum. In another embodiment this invention further comprises a process for preparing a gellan gum composition useful for coating a placebo or a coated pharmaceutical tablet which comprises the steps of admixing gellan gum and water under effective shear conditions to prepare an aqueous gellan gum coating composition thereof. In another embodiment this invention further comprises preparing the aforementioned aqueous gellan gum coating composition and applying the same in an adherent fashion to a placebo or a tablet containing a pharmaceutical whereby a gellan gum coated placebo or gellan gum coated pharmaceutical tablet is formed and thereafter drying the same. In yet another embodiment of this invention, this invention comprises a method of treating a patient in need of treatment which comprises administering to the patient a therapeutically effective amount of a coated tablet, wherein said coated tablet comprises a tablet coated with gellan gum and which contains a therapeutically effective amount of a therapeutically effective drug beneficial to said patient. Other embodiments of this invention are included herein and are described in more detail hereinafter.
Gellan gum useful herein is that produced by inoculating a carefully formulated fermentation medium with the microorganism Sphingamonas elodea (ATTC 31461). Gellan Gum is available from Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, Mo. 63167, USA. Typical brand names include KELCOGEL(copyright) and GELRITE(copyright). Gellan gum useful herein includes any form available form such as but not limited to, non-clarified, clarified, and partially-clarified native, deacetylated and partially deacetylated forms as well as mixtures thereof and the like. Kelcogel(copyright) and Gelrite(copyright) are registered trademarks of Monsanto Company. Gellan gum may be prepared according to the methods disclosed in U.S. Pat. Nos. 4,326,052 and 4,385,123 both of which are incorporated herein their entirety by reference.
Optional components of the gellan gum aqueous coating composition of this invention may include but are not limited to a color additive(s) and/or other coating polymers as will be readily apparent to those of skill in the art in particular after reading this specification. A typical plasticizer is glycerine although any equivalent or substantially equivalent plasticizer may be satisfactorily employed herein if desired.
The scope and utility of the present invention is not limited to any active ingredient. Active ingredients which may be effectively coated using this invention are not limited and include illustratively pharmaceutical active ingredients and over-the-counter drugs (including vitamins and nutritional supplements and the like) such as those typically delivered in a tablet dosage form. Examples include but are not limited to analgesics and antiphlogistics such as aspirin, acetaminophen, phenacetin; steroids including antinflammatory steroids; enzymes, proteins, antibiotics or antimycrophotics including penicillin and its derivatives; anesthetics, vasodiolators such as nitroglycerin, anticarcinogins, sulfonamide drugs, sedatives, tranquilizing and hypnotic agents, bronchial-dilating agents, potassium chloride, mixtures thereof and the like.
The process for preparing a coated placebo or a coated (pharmaceutical) tablet comprising an active drug herein comprises the steps of admixing gellan gum and water under effective shear, heat and ionic conditions to prepare an aqueous gellan gum coating composition and applying the aqueous gellan gum coating composition in an effective fashion to a placebo or to a tablet such as one comprising a pharmaceutical whereby a gellan coated placebo or coated pharmaceutical tablet is formed. A drying step typically occurs and typically follows.
The aqueous gellan gum coating composition useful to coat tablets is preferably admixed in any suitable container or the like prior to applying the gellan gum composition to or on a tablet to be coated. Initially the gellan gum and water are admixed and further mixing is carried out under effective shear to form an aqueous tablet coating composition. Typically the gellan gum coating aqueous composition prior to application of such effective shear will have a viscosity in the range from about 44 cps. to about 55,500 cps. and preferably from about 2200 to about 50,000 cps although gellan gum compositions having greater and lesser viscosities may sometimes be employed depending on a number of factors.
If desired, gellan gum compositions comprising gellan gum and/or gellan gum and one or more of a another ingredient such as a polymer such as, but not limited to, those selected from the group consisting of hydroxypropyl celleulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sugar, aspartame, maltodextrin, tapioca dextrin, modified food starches, polyvinylpyrolidone, mixtures thereof and the like may be employed in this invention. As employed herein, the term xe2x80x9cgellan gumxe2x80x9d includes gellan gum and/or compositions of gellan gum with one or more of these polymers or a sugar.
The aqueous gellan gum composition of this invention may be mixed in or by any suitable mixing system preferably until substantially complete mixing has been accomplished. Some heating may be necessary to achieve dispersion and hydration of gellan gum. The amount of shear preferably employed is an effective amount, i.e., which produces a well mixed homogenous gellan gum composition. The aforementioned admixing can be carried out by any convenient means including but not limited to use of a propeller or stirrer system although generally stirring by a convenient mechanical means is acceptable. Other forms of mixing can be employed.
Optionally, if desired, various other ingredients may be employed in the gellan gum aqueous composition include any ingredient which is compatible or can be made compatible with an aqueous gellan gum composition useful to coat tablets of this invention, (such as, but not limited to, colors, color system(s), flavor(s), sweetener(s), mint(s), fragrance(s), plasticizer(s), active ingredient(s) and mixtures thereof and the like).
The gellan gum aqueous composition is preferably applied to the tablet(s) to be coated in a batch, semi-continuous or continuous process or some combination thereof in a manner which produces a satisfactorily uniformly coated tablet. The gellan gum composition may be applied to tablets to be coated using any satisfactory application and drying system or combination of some application system and some drying system. The combination is not critical nor is the arrangement of equipment.
The amount of gellan gum in the gellan gum aqueous composition useful for coating tablets is about 0.1% to about 10% and preferably from about 0.25% to about 5% by weight gellan gum of the total gellan gum aqueous composition although greater and lesser amounts of gellan gum may be employed if desired. A most preferred range is about 0.075% to about 3%.
During application of the gellan gum aqueous composition to the tablet to be coated, the temperature of the gellan gum aqueous composition is preferably in the range from about 25xc2x0 C. to about 45xc2x0 C. although greater or lesser temperatures may be employed if desired. It is preferred that the gellan gum composition be maintained in a solution or dispersion or an applicable state during its coating application to the tablet(s) to carry out this invention.
Historically those of skill in the art have considered a composition having a viscosity of about 1,000 centipoise (cps) as being at the upper bound as regards usefulness as a coating composition due to that high viscosity. Since an aqueous composition comprising gellan gum (1.8% by weight gellan gum) and water has a viscosity of about 28,460 cps at a temperature of about 30xc2x0 C., those of skill in the art would not have considered such a composition useful to coat tablets and would have been steered away from it for this invention. Now, however, the inventors have surprisingly discovered that despite the high viscosity of a gellan gum composition at room temperature that such compositions are very useful to coat tablets as the invention herein provides.
Gellan gum may be coated onto tablets which are uncoated or are those tablets which have been coated with one or more prior coatings (overcoating) of an acceptable coating composition which allows adherency with gellan gum. An initial coating may comprise one or more polymers such as cellulosics, dextrins, acrylics, any colors or other pharmaceutical coating material. A gellan gum composition may be employed as a primary coating on a tablet, as a secondary coating on a tablet, or as a tertiary coating if desired. One or more coating applications of gellan gum may be made to a coated or uncoated tablet in accordance with this invention, although typically one coating is effective and is preferred. If desired, a gellan gum coating may be applied to a tablet in accordance with the invention in an instance wherein a protective coating is desired, for example to protect coated or uncoated tablet from physical damage.
Typically the amount of gellan gum which is coated onto tablets in practicing this invention is that amount which provides a gellan gum coated tablet having a weight gain (during coating) from about 0.025% to about 10% weight percent of the total tablet weight and preferably from about 0.05% to about 5% weight percent of the total tablet weight although larger and smaller weight percents may be employed if desired. Typically this amount of gellan gum is that amount which is necessary to provide an effective or desired coating.
Neither the tablet shape nor the tablet size are critical. Preferred shapes and sizes are those which can be effectively consumed by a human or animal recipient with relative ease. Preferable sizes of tablets include but is not limited to those tablets which are about xc2xc inch to about xc2xe inch in size and weigh from about 100 to about 1.5 grams each although tablets may be employed which are larger or smaller in size and of lighter and heavier weight if desired. Preferred shapes are round or oval; however other shapes may be employed if desired.
Preferred tablets are medicinal tablets for humans or animals. The tablets include but are not limited to tablets of any convenient composition which may or may not contain any pharmaceutically effective drug vitamin or nutrient or drugs suitable for human and/or animal consumption. A gellan gum coating may be employed on tablets which are placebos or blanks. Tablets useful herein include but are not limited to tablets which are uncoated or have been coated one or more times. In one embodiment a gellan gum coating may be the only coating and may comprise a first coating or a second or a third coating.
Illustrative colors and colorants useful herein include without limitation, pigments, dyes, lakes and oxides (including titanium dioxide) and the like, may be optionally employed with gellan gum used in practicing this invention. The gellan gum aqueous composition may optionally contain a suitable color or colorants for application to a colored or noncolored coated or uncoated tablet.
Tablets to be coated according to this invention may be colored, neutral or have their natural color or may be absent color. If one of more colors, dyes lakes, or pigments or mixtures thereof are employed in a gellan gum coating composition herein, such as for example, an FDA certified color, dye, lake, or pigment, the color or combination of colors is not critical and may be selected by those of skill in the art based upon a need at the time of the coating operation. Examples of suitable pigments which are useful in this invention include, without limitation, FDandC and DandC lakes, titanium dioxide, magnesium carbonate, talc, pyrogenic silica, iron oxides, channel black, insoluble dyes and mixtures thereof and the like. Also, nature pigments such as riboflavin, carmine 40, curcumin, annatto, mixtures thereof and the like are acceptable herein. Other examples of pigments suitable herein include, without limitation, these disclosed in Jeffries U.S. Pat. No. 3,149,040 and Butler et al., U.S. Pat. No. 3,297,535, as well as in Colorcon U.S. Pat. No. 3,981,984. These three patents are incorporated herein by reference in their entirety. In the absence of a colorant, the gellan gum composition typically produces a clear or substantially clear coating on a coated tablet.
As employed herein, the term xe2x80x9ctabletxe2x80x9d includes without limitation, tablet, particle, micronized particle, particulate, pellet, pill, core, powder, granule, granulate, small mass, seed, specks, spheres, crystals, beads, agglomerates, mixtures thereof and the like. Typically the preferred tablet will be in a form sufficiently stable physically and chemically to be effectively coated in a system which involves some movement of the tablet, as for example in a fluidized bed, such as in a fluidized bed dryer or a side vented coating pan, combinations thereof and the like. Virtually any tablet, placebo, the latter typically lactose or sugar or mixtures thereof and the like, is acceptable herein as a tablet to be coated in the practice of this invention.
Tablets coated according to this invention have a high gloss. Typically the gloss is in the range from about 200 to about 400 and preferably from about 250 to about 350 although greater or lesser gloss may be employed if desired. As referred to above, gloss is measured or characterized typically by use of a Tricor Systems, Inc., Model 805A, Surface Analysis System. Tablets of this invention typically have one or more enhanced properties such as higher gloss, better mouthfeel, non-tackiness, being swallowable with little or no accompanying liquid, better taste and the like.
The gloss resulting from gellan gum coating of this invention is superior in shine to conventional film coatings presently used in the industry. Measurements of gloss on polymer coated tablets and commercial products were well below the gloss imparted with gellan gum prepared in accordance with this invention as measured at TRICOR Systems. Gellan gum coatings of this invention impart this gloss at weight gain levels that are considerably lower than existing and accepted alternatives. As a result of this high gloss from comparatively lower weight gains brought about by this invention, gellan gum is an attractive alternative to existing aqueous form coatings.
This characteristic high gloss from low weight gains also makes gellan gum an attractive alternative to sugar coating processing currently used in the industry. Sugar coating processes currently use multiple materials, extended processing times and multiple material handling steps. Superior gloss can be achieved with gellan gum at a fraction of the weight gain now required in sugar coating. This lower material requirements results in glossy tablets that can be manufactured much faster than current products and can also be formulated to produce a smaller, easier to swallow dosage.
As employed herein, the term xe2x80x9cadherentxe2x80x9d means that the gellan gum coating effectively adheres to the coated tablet until consumption by a patient or animal to enable effective release of the active ingredient therefrom so that the active is effectively made available to the patient""s biological systems to provide therapeutic value.
Although the gellan gum coating composition of this invention will initially be an aqueous composition, the tablet coating will preferably be dried or substantially dried prior to, upon its exit or removal from the coating application system or at sometime in preparing coated tablets. The coated tablets may be placed in suitable packaging then if desired.
The amount of coating provided to the surface of the tablet is an effective amount and is typically that amount which provides a minimum effective coverage of the exterior surface area of the tablet, although this invention also encompasses those instances where there is partial coverage of the exterior surface as well.
If desired, one or more layers of gellan gum coating may be employed using this invention. Those of skill in the art will be able to determine the extent of any layering depending on the drug, tablet size, and its physical and chemical and therapeutic properties and characteristics from a reading of this specification and using their skill in the art.
It is preferred that coating be continuous or nearly continuous and over the surface of the tablet. An effective depth of coating is provided for retention. It is also desired that the tablet coatings herein be somewhat resilient with respect to handling, to peeling and to flaking and being rubbed off the coated tablet.
As referred to above, application of the gellan gum aqueous composition as a coating to the tablet is preferably carried out by placing a tablet capable of receiving and adhering a gellan gum tablet coating composition of this invention in any acceptable coating application system. An acceptable coating application system is illustratively any system which has the capability to apply a gellan gum coating composition of this invention to a tablet to provide an effectively, preferably uniformly coated tablet. For example, an acceptable coating application system includes without limitation, a plain fluid bed system (i.e., one without any xe2x80x9cWursterxe2x80x9d type insert), including a fluid bed spray tower of any reasonable size and design and systems similar thereto in function and utility.
Air Suspension Coating systems useful here as an illustrative application system include those described in Ullman""s Encyclopedia of Industrial Chemicals, Volume A16 pages 583-584 (1990) which includes a description of the Wurster process. Ullman""s Encyclopedia of Industrial Chemicals, Volume A16 pages 583-584 (1990-1996) is incorporated herein by reference in its entirety. This incorporation includes the chapter Microencapsulation authored by Christopher A. Finch of Pentafin Associates, Weston Turville, AYLESBURY HP 22 5TT, UK.
Also, acceptable for use to prepare coated tablets of this invention are illustratively a variety of side vented coating pans, spray dryer(s), continuous coating pans, and conventional coating pans, such as those with systems for mechanically providing the gellan gum composition to a tablet in an effective manner using mechanical means as for example by spray nozzles or the like. Also acceptable as a spray tower system is a conventional fluid bed tower equipped with a suitable spray apparatus. Any application system capable of applying a composition of this invention to a tablet is an acceptable system for coating tablets employing the aqueous gellan gum coating composition of this invention. As the coating system is not critical, any size coating system is acceptable. Batch and continuous processes, semi-continuous and suitable variations thereof are envisioned without limitation.
The xe2x80x9cWursterxe2x80x9d type fluid bed dryer typically comprises a cylindrical outer vessel having a perforated floor through which a heated gas passes upwardly to heat and fluidize a batch of tablets or particles fed to or formal therein. A concentric, open ended inner cylinder is suspended above the center of the perforated floor of the outer vessel. A spray nozzle, or projecting part, centered beneath the inner cylinder sprays a solution of the coating material upwardly into the inner cylinder as the fluidized materials pass upwardly through the spray in the inner cylinder. The particles circulate upwardly though the center of the inner cylinder and downwardly between the inner and outer cylinder. The air that fluidizes the particles also serves to vaporize the water causing the composition to deposit as a film or coating onto the surface of each particle. After repeated passes through the coating zone in the inner cylinder, a sufficient thickness of polymer accumulates over the entire surface of each particle as to coat each particle. A description of an acceptable xe2x80x9cWursterxe2x80x9d type fluid bed dryer is found in J. Am Phar. Assoc, Sci. Ed. Vol 48, (1959) Air Suspension Technique of Coating Drug Particles by Wurster, Dale E. and Preparation of Compressed Tablet Granulations by the Air Suspension Technique II, Wurster, Dale E, Sci Ed Vol 49 (1960) both of which are incorporated herein in their entirety by reference. In operation of the dryer, the operator will typically have the tablets discharged when the desired amount of coating has been applied to the tablets. This is generally based on the amount of coating composition sprayed in the dryer from which based on prior experience, the amount of weight gain (%) of the tablets during coating can be determined. Electronic or equivalent controls are typically installed on the dryer to regulate the process such as regulating the temperature of the inlet air and the amount of such inlet air and its pressure.
In side vented coating pan systems, as the material inside is coated it increases in size and weight. Generally the materials to be coated accumulate adjacent an end wall and along a side wall of the drum in the system. As the drum rotates, the material is tumbled and is coated with a coating composition from one or more spray nozzles. Initially the material may form a mass and as the material is sprayed and increased in size the large particles migrate away from the end wall and cannot penetrate the mass of smaller particle adjacent the end wall. Eventually, substantially all of the material is uniformly coated a such that the material forms a new mass wherein the particles are slightly larger than the original mass formed by the uncoated particles. The process repeats itself such that the particles are coated with additional composition from the spray nozzle, thereby again increasing in size and weight and migrating away form the end wall. The cycle continues until the particle achieve a desired uniform size.
Particularly usefull self contained side vented coating pan system in this invention are available under the Accela Cota brand sold by Thomas Engineering Incorporated, 575 West Central Road, Hoffman Estates, Ill. 60195-0198, U.S.A. Various size pans may be satisfactorily employed herein and include without limitation 15, 24, 48 and 60 inch pans, if desired. The size of the pan and dryer are not critical. The Compu Lab model sold under the Accela Cota brand works well for laboratory size charge (feed) quantities. Those of skill in the art will recognize that various size pans may be employed depending on the amount of materials to be coated and other coating operations.
The Accela Cota brand side vented coating pan system comprises a rotating drum and as the drum is rotated containing the tablets to be coated, the coating composition is applied to the tablets by means of one or more nozzles positioned within the rotating drum so as to direct the coating composition to the tablets in the bed. As the pan is rotated and the coating composition is further applied to the tablets, the tablets achieve a desired coating. This apparatus is also a dryer for substantially drying the tablets as the tablets are coated. The side wall of the drum is perforated and a flow of air is provided into the drum through apertures for drying the coating composition on the tablets. A system is also provided on the apparatus for removing the outlet air and for removing the coated tablets.
The nozzles of this side vented coating system are preferably adjustable and may be positioned nearer to and closer to the bed of tablets to be coated depending on the conditions of use and the desired coating composition quality and quantity, among other factors. Those of skill in the art will recognize that the distance of the nozzle or nozzles from the bed is important and may be adjusted to provide optimum coating compositions. In operation such nozzle placement distances will be an effective distance and will be selected from a plurality of available positions and will depend on the tablets being coated, the coating compositions, the degree of coating desired and other conditions of the particular coating operation, among other factors.
Those of skill in the art will recognize that one or more nozzles may be employed as desired to provide optimum coating. The number of nozzles is not critical and may be varied as needed depending on the coating operation and other factors. The nozzle throat diameter is typically from about 0.028 inch to about 0.100 inch although, greater and smaller throat diameters may be employed. A nozzle throat diameter of somewhere about 0.040 inch is preferred although that size is not critical. The nozzle(s) is preferably aimed perpendicularly or nearly perpendicular to the bed although other direction(s) of aim may be employed if desired. Those of skill in the art will recognize that the pan may be rotated at a speed selected from a plurality of operating speeds. The pan may be stopped after the material has been coated and the matter removed.
In general, an effective nozzle distance for applying a coating to a tablet using a side vented pan coating system is in the range from being positioned less than about a xc2xc inch from the bed to about 15 inches and preferably from about 8 to about 12 inches although greater of lesser nozzle distances may be employed if desired depending on the weight of tablets charged into the pan and coating system composition and other factors.
If desired, the same or a similar coating application system can be employed for both a first and a second or sequential coating applications or different coating application systems may be employed for a first or second or more coating applications. If desired, the same coating application system can be used to apply a first and second or more coatings with or without removal of the tablets from such a system between the first and second or more coatings.
While illustrative useful application systems have been described herein, those of skill in the art will recognize that such description is provided to provide information as to the possible application and use herein in accordance with this invention. Those of skill in the art will recognize that the actual operation of any such application system will vary and may be varied from xe2x80x9ctext bookxe2x80x9d type description of such operation in according with the parameters and conditions of any desired operation, among other factors. Configurational and design changes may be made on such applications systems and operating parameters may be varied.
The gellan gum coated tablets of this invention may be internally consumed by humans and animals in a typical customary manner.